The studies proposed here are aimed at applying the techniques of molecular genetics to further elucidate the roles of inherited defects, environmental influences and genomic instability in the etiology of colorectal cancers in a defined population. Eighty families, identified from population-based cancer registries, with a high incidence of colorectal cancer that is likely to be of genetic etiology, will be included in genetic linkage studies. Linkage to prominent candidate genes will be tested, particularly the recently detected predisposing gene on chromosome 2, called FCC for familial colon cancer. Efforts will be directed toward using genetic linkage analysis to refine the location of this chromosome 2 gene, to facilitate positional cloning. Somatic changes in the tumors from individuals in the linkage families will be examined to test for the possibility of gene-gene interactions influencing the carcinogenic pathway. Somatic changes in precancerous lesions (polyps) from unrelated individuals with characterized environmental risk factors will also be examined to detect possible correlations. A newly recognized phenomenon of genome-wide somatic change, called RER, for replication error, will be characterized in tumors from the candidate linkage families and in the polyps from environmentally assessed cases. Published studies suggest that RER is found in essentially all tumors resulting from a defect in the FCC gene. About 15% of all colon tumors from "random" series exhibit RER, suggesting that germline or somatic defects in the FCC gene on chromosome 2 or related gene(s) may be significantly involved in the etiology of this fraction of all colon tumors. We propose further molecular analyses for defining the frequency and role of RER in colorectal neoplasia and its association with inherited defects or environmental influences. We will examine the molecular mechanism underlying RER, as understanding of this may lead to a screening test for individuals with germline FCC defects and may help to identify environmental factors that promote it. Project l of this cooperative effort is a genetic epidemiological study of familial colorectal cancer that will include the ascertainment of the genetic linkage families included in the present proposal. Project 2 is the central effort for examining gene-environment interactions in colorectal polyps. This is Project 3.